1. Field of Invention
The present invention relates to antiviral agents, and more particularly, to multivalent antiviral agents that bind to trimeric gp120 complexes thereby blocking the CD4 binding site on the gp120 complexes and inhibiting the attachment and entry of HIV through gp120-CD4 interactions.
2. Description of the Related Art
The human immunodeficiency virus (HIV) has been implicated as the primary cause of the slowly degenerative immune system disease termed acquired immune deficiency syndrome (AIDS). In humans, HIV replication occurs prominently in CD4 T lymphocyte populations, and HIV infection leads to depletion of this cell type and eventually to immune incompetence, opportunistic infections, neurological dysfunctions, neoplastic growth, and ultimately death.
The HIV viral particle comprises a viral core, composed in part of capsid proteins, together with the viral RNA genome and those enzymes required for early replicative events. Myristylated gag protein forms an outer shell around the viral core, which is, in turn, surrounded by a lipid membrane envelope derived from the infected cell membrane. The HIV envelope surface glycoproteins are synthesized as a single 160 kilodalton precursor protein, which is cleaved by a cellular protease during viral budding into two glycoproteins, gp41 and gp120. gp41 is a transmembrane glycoprotein and gp120 is an extracellular glycoprotein, which remains non-covalently associated with gp41, in a trimeric or multimeric form. Data from recent structural and biochemical studies have demonstrated that the HIV-1 envelope glycoprotein gp120 is displayed as a gp41-associated trimer and forms envelope spikes on the surface of HIV virions (14-18). Recent electron tomography further confirmed this theory (19).
It is known that the initial step of HIV entry is characterized by the interaction of HIV-1 envelope glycoprotein gp120 with host receptor CD4. The CD4 binding site on gp120 is centered on a conserved, hydrophobic pocket denoted the “Phe43 cavity.” It has been demonstrated that molecules targeting the conserved CD4-binding pocket, such as soluble CD4, CD4 mimetic proteins and HIV-neutralizing antibody b12, are potent inhibitors against HIV infection (6-13).
Although considerable effort has been expended on the design of effective therapeutics, currently no curative anti-retroviral drugs against AIDS exist. The new treatment regimens for HIV-1 include a combination of anti-HIV compounds, which target reverse transcriptase (RT), such as azidothymidine (AZT), lamivudine (3TC), dideoxyinosine (ddl), tenofovir, nevirapine, efavirenz, or anti-HIV compounds which target HIV protease such as saquinavir, nelfinavir, indinavir, amprenavir, and lopinavir. Unfortunately, the development of viral resistance occurs in a significant number of treated patients using these compounds. This combined with the development of anti-retroviral drug induced toxicity continues to limit the overall impact of current available treatments.
Thus, the toxicity and emergency of drug-resistant viruses associated with current drug regimen prompts development of new drugs that act with a different mode of action and with improved anti-HIV potency. Accordingly, there is a need for new drugs that blocks HIV attachment and entry at the stage of HIV envelope binding to host receptor CD4.